tbuckley/cabot-search huggingface dataset:
Antibody-drug conjugate (ADC) joint disposition properties and their clinical utilities for comparative assessments in terms of favorable pharmacokinetic (PK) characteristics.
Authors: Jason H. Williams, Kai H. Liao, Santhosh Palani, Donghua Yin, Xu Meng
Journal: Journal of Clinical Oncology (2022)

e15005 Background: PK characterization of ADCs is often fragmented using separate analyses of individual analytes. As such it is difficult to compare among ADCs in terms of PK characteristics critical for understanding the fate of an ADC complex as a whole and its clinical implications. While several integrated PK models have been applied to clinical datasets, these have been mostly for the purpose of identifying covariate effects on PK parameters. In this abstract, we propose 3 joint disposition metrics for integrated PK characterization of ADCs based on a combination of concentrations of ADC, payload (PL), conjugated payload (CPL), and total mAb (TAb, ADC plus unconjugated mAb) in the blood, and for defining what are favorable PK characteristics for ADCs. Methods: The joint disposition metrics representing linker stability (AUC mAb /AUC Tab ), therapeutic exposure ratio (CL PL /CL ADC ) and effective drug-antibody ratio (DAR) (AUC CPL /AUC ADC ), were derived mathematically from a framework of typical ADC designs and verified via modeling approaches using PK data of 3 clinical candidates, an anti-Trop2 ADC (PF-06664178) [King GT, et al. Invest New Drugs 2018;36(5):836-847], an anti-Notch3 ADC (PF-06650808) [Rosen LS, et al. Invest New Drugs 2020;38(1):120-130], and an anti-PTK7 ADC (PF-06647020) [Maitland ML, et al. Clin Cancer Res 2021;27(16):4511-4520]. Furthermore, the joint disposition metrics were calculated for a number of FDA-approved or otherwise well documented ADCs, which were selected as the information on ADC, payload and TAb analytes is available, to examine their clinical utilities in assessing among ADCs in terms of favorable PK characteristics. Results: The validity of the joint disposition metrics was demonstrated and verified for integrated PK characterization of ADCs. Estimates of the joint disposition metrics, for the linker stability, therapeutic exposure ratio and effective DAR, were obtained for the selected ADCs products and candidates (Table below), consistent with the expectation based on clinical experience. Conclusions: Three joint disposition metrics were derived for integrated PK characterization of ADCs using conventional PK analytes. Their clinical utilities were explored in assessing among ADCs in terms of favorable PK characteristics. Analyses of additional ADCs may be needed to further validate these metrics for broader usage.[Table: see text]
Dalpiciclib in combination with letrozole/anastrozole or fulvestrant in HR+/HER2- advanced breast cancer: A phase Ib study.
Authors: Qingyuan Zhang, Pin Zhang, Min Yan, Xi Yan, Xian Wang, Yuanting Gu, Xiujuan Qu, Shaorong Li, Guoying Xu, Wenhui Yang, Xiaoyu Zhu, Xiaojing Zhang, Binghe Xu
Journal: Journal of Clinical Oncology (2022)

1066 Background: Dalpiciclib (Dalp; SHR6390) is a novel cyclin-dependent kinase 4/6 inhibitor which showed tolerability and preliminary clinical activity as monotherapy for pretreated advanced breast cancer (ABC). Here we conducted a multicenter, phase 1b trial to further assess the safety, pharmacokinetics and efficacy of Dalp in combination with endocrine therapy (ET) in HR+/HER2- ABC. Methods: 5 cohorts of patients with HR+/HER2- locally recurrent or metastatic BC and any menopausal status were enrolled (~15 patients/combination regimen). Patients without prior treatment for ABC (cohort1/2) were given Dalp (125 or 150 mg po qd, d1-21, q4w) plus letrozole (LTZ; 2.5 mg po qd) or anastrozole (ATZ; 1 mg po qd); patients who progressed after ET (cohort 3-5) were given Dalp (125, 150, or 175 mg po qd, d1-21, q4w) plus fulvestrant (Fulv; 500 mg im, cycle 1 d1, d15, then d1 q4w). The primary endpoint was safety. The data cutoff date was Sep. 20, 2021. Results: 58 patients received Dalp plus LTZ/ATZ and 46 received Dalp plus Fulv. No maximum tolerated dose of Dalp was reached with LTZ/ATZ or Fulv. Across all cohorts, 75.0%-93.8% of patients had a grade ≥3 treatment-related adverse event (TRAE), with the most common being neutropenia (grade 3, 40.0%-87.5%; grade 4, 4.2%-46.7%) and leukopenia (grade 3, 33.3%-80.0%; grade 4, 0%; Table). Treatment-related serious AEs occurred in 2 (3.4%) patients with Dalp plus LTZ/ATZ and none with Dalp plus Fulv. At the tested dose levels, steady-state areas under the concentration curve and peak concentration of Dalp increased with dose in combination with LTZ/ATZ or Fulv. Dalp 150 mg was associated with a numerically higher objective response rate in both ET-untreated (67.6%, 95% CI 49.5-82.6) and ET-pretreated (53.3%, 95% CI 26.6-78.7) patients per investigator. The median progression-free survival with Dalp 150 mg was 20.3 mo (95% CI 16.9-not reached [NR]) and 16.7 mo (95% CI 1.9-24.1) in ET-untreated and ET-pretreated patients respectively. Conclusions: Dalpiciclib plus letrozole/anastrozole or fulvestrant showed an acceptable safety profile, with hematological toxicities as the most common TRAEs. The recommended phase 3 dose of dalpiciclib was 150 mg. Together with the promising anti-tumor activity observed with the combination therapy in HR+/HER2- ABC, further trials are warranted. Clinical trial information: NCT03481998. [Table: see text]
EPHB1 mutation predicts survival from treatment with immune checkpoint inhibitors and correlated with higher TMB and immune infiltrates in mCRC.
Authors: Jinlin Cai, Dandan Fan, Yaoxu Chen, Mengli Huang
Journal: Journal of Clinical Oncology (2022)

e15559 Background: Colorectal cancer has become a common gastrointestinal tumor. Immune checkpoint inhibitors (ICIs) including pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, the research exploring the association between gene mutation and clinical benefit is limited. Studies have shown that EPHB1 mutation in the NK cell-related pathway involved in the anti-cancer immune response and associated with survival of NSCLC patients, suggested that EPHB1 may be related to immune microenvironment and tumor immunity. However, the association between EPHB1 mutation and TMB or survival in metastatic Colorectal Cancer (mCRC) is unknown. Methods: Genomic and survival data of mCRC patients administrated with ICIs was retrieved from publicly accessible data(Pancancer.Samstein2018.NGS.1661),the association between EPHB1 mutation and overall survival(OS) was analyzed using Kaplan-Meier curves and log-rank tests. At the same time，the association between EPHB1 mutation and TMB was also analyzed in this public immunotherapy-treated cohort, Wilcoxon test was used for the comparison of TMB. In addition, genome and immune cell infiltration data of 149 patients with Colon Adenocarcinoma (COAD) was obtained from The Cancer Genome Atlas (TCGA). The correlation analysis between immune cell infiltration and EPHB1 mutation status was further analyzed by CIBERSORT-ABS. Statistical significance was set at p = 0.05. Results: 7.3%(8/109) patients in the clinical cohort harbored EPHB1 mutation. Survival analysis in the public cohort demonstrated that EPHB1 mutation resulted in significantly longer OS (14 vs 8 months; HR, 0; p = 0.03) in mCRC patients treated with ICIs. Moreover, EPHB1 mutation was associated with higher TMB in public cohort (p = 0.0004). Furthermore, the correlation analysis between immune infiltration and EPHB1 mutation status in mCRC showed that CD8+T cells, activated memorial CD4+T Cell, M1 macrophages increased significantly in EPHB1 mutation patients(p = 0.023, p = 0.0079, p = 0.034). Conclusions: EPHB1 mutation may serve as a potential positive biomarker of ICIs in mCRC since it relatively correlated with higher TMB. In addition, the up regulation of CD8+T cells, activated Memorial CD4+T Cell as well as the M1 macrophages may be a potential mechanism for the better efficacy of ICIs in patients with EPHB1 mutation.
Differences in tumor microenvironment between HER2-positive and HER2-negative breast cancer.
Authors: Chang Gong, Qun Lin, Yinghuan Cen, Xiaolin Fang, Yu Shi, Letian Chen, Qing Luo, Zhuxi Duan
Journal: Journal of Clinical Oncology (2022)

e12562 Background: The tumor microenvironment of breast cancer is extremely complex, which containing different types of lymphocytes, macrophages, NK cells and other immune cell subtypes. At present, the relationship between immune cell subtypes and molecular subtypes of breast cancer is still unclear. Methods: Tumor tissue samples of 20 breast cancer patients were collected from January 2020. Then the density (number of positive cells/mm 2 ) and ratio of immune cells in intratumoral area and stromal area were detected by multiple fluorescence immunohistochemistry (mIHC), the detection range was included CD3+T cells, CD4+T cells,CD8+T cells,PD-1+CD8+T cells,Tregs,M1/M2 tumor associated macrophages (TAM), PD-L1+CD68+TAM,B cells,CD56bright NK cells and CD56dim NK cells and so on. The immune cell subtypes of all area were included both intratumoral area and stromal area. Graphpad prism (version 7.01) was used for t test and the statistical significance was set at p=0.05. Results: These 20 patients were divided into two groups, HER2 positive (n=8) and HER2 negative group (n=12). The density of CD3+T cells in all area (including intratumoral area and stromal area) of tumor tissue in HER2 positive breast cancer patients were significantly higher than that of HER2 negative breast cancer patients (median density, HER2 positive group vs. HER2 negative group=2998 vs. 1520/mm², p=0.031) as well as the CD8+T cells (median density, HER2 positive group vs. HER2 negative group=536 vs. 175/mm², p=0.015). Meanwhile, the density of Tregs in all area of tumor tissue in HER2 positive breast cancer patients was also significantly higher (median density, HER2 positive group vs. HER2 negative group=119 vs. 27/mm², p=0.022).However, there was no significant difference in the other subtypes of immune cells infiltrated in tumor tissue between HER2 positive and HER2 negative samples, such as CD4+T cells, M1/M2 macrophages, B cells and so on (p＞0.05). Conclusions: Our research indicates that the patterns of immune cell subtypes in different types of early breast cancer are different. Further exploration of the immune microenvironment in different molecular types of breast cancer may provide additional targets for immunotherapy.
Hypokalemia, hypomagnesemia, and hyponatremia are associated with acute kidney injury in patients treated with cisplatin.
Authors: Louis Pinard, Jean-Philippe Adam, Miguel Chagnon, Guillaume Bollée, Denis Soulieres
Journal: Journal of Clinical Oncology (2022)

e24105 Background: Cisplatin-associated acute kidney injury (C-AKI) is common. Predictive factors of C-AKI include age &gt; 60 years, hypertension, cisplatin dose, diabetes, and serum albumin &lt; 3.5g/L. The association between C-AKI and hypokalemia, hypomagnesemia or hyponatremia has not been well characterized to date. Methods: Data from a previous retrospective observational study was obtained. Patients who received at least one dose of cisplatin between September 2010 and December 2016 at the Centre Hospitalier de l’Université de Montréal were included. Patients were separated into 3 groups with similar cisplatin doses and schedules. Group A received cisplatin 60-100 mg/m 2 q 3 weeks with laboratories before day 1, group B received cisplatin 60-75 mg/m 2 q 3 weeks with laboratories before days 1 and 8 of each cycle and group C had weekly cisplatin 40 mg/m 2 and laboratories. Association between hypomagnesemia, hypokalemia, hyponatremia, and risk of AKI, as defined by KDIGO criteria, was determined using a counting process specification of Cox’s regression models. These were used to estimate hazard ratio (HR) of AKI incidence with 95% confidence intervals (CI) of patients with and without cisplatin-induced electrolyte disorders. Estimates were adjusted for confounding factors such as volume of hydration (3 or 4 L), fluids (D5/0.45 NS or NS), age, sex, presence of furosemide and mannitol. Results: A total of 1305 patients were separated in group A (714 pts), B (205 pts) and C (386 pts). The proportion of patients with at least one event of hypokalemia, hypomagnesemia or hyponatremia was lower in group A (29.1%, 57.7% and 36.3%) compared to group B (43.4%, 66.8%, 60.0%) and group C (48.7%, 78.6%, 50.8%). The incidence of all grade C-AKI was 35.7% (group A), 46.8% (group B), 18.2% (group C). The HR of C-AKI based on each electrolyte disorder per group is presented in table I. Conclusions: The presence of one event of hypokalemia, hypomagnesemia, or hyponatremia was significatively associated with increased risk of C-AKI only in group A. This could be related to the higher average dose per cycle in this group. Other studies are needed to characterize the presence of an electrolyte disorder as a risk factor that can predict the risk of C-AKI in this subpopulation. [Table: see text]
Palliative care pilot initiative for transplant patients: The Westchester Medical Center experience.
Authors: Kelley Mowatt, Stephanie Danyko, Mariama-Seray Barrie, Sandra Gordon, Kathy Marcotte, Erica Rotundo, Adam Schoenfarber, Tauseef Ahmed, Delong Liu, Karen Seiter, Mara Lugassy, Amir S. Steinberg
Journal: Journal of Clinical Oncology (2022)

e19050 Background: It is well known HCT recipients experience multiple symptoms affecting quality of life. Emerging data supports the role palliative care can play in mitigating these issues. Our cellular therapy team collaborated with the Palliative Care team on a pilot project incorporating their expertise into the management of our new allogeneic transplant patients. We chose this group of patients given their increased needs relative to other cellular therapy recipients (i.e. autologous, CTL) and our institution’s available resources. Methods: Patients admitted to the HCT unit for allogenic stem cell transplant underwent palliative care consult during their conditioning regimen. During the initial palliative care visit, performed by a specialist palliative care nurse practitioner, patients underwent comprehensive assessment of physical symptoms, psychosocial distress, and overall quality of life. Patients were then followed during hospitalization by members of the palliative care team including Nurse Practitioner, Social Worker and Chaplain, to address identified needs and support both the patient and their family. The palliative care team provided daily communication and recommendations to our inpatient HCT team. Results: Patient one was a 61-year-old man with intermediate risk MDS who underwent a reduced intensity conditioning regimen of busulfan, fludarabine, and alemtuzumab. His transplant was complicated by delirium and anorexia. Patient two was a 63-year-old man with AML who underwent a reduced conditioning regimen of the same combination. His transplant was complicated by bone pain and insomnia. Patient three was a 70-year-old woman with AML who also underwent a reduced conditioning regimen. Her transplant was complicated by severe mucositis and gastric reflux. Conclusions: Allogeneic stem cell transplant patients experience a multitude of symptoms and psychosocial distress. With the help of a dedicated palliative care assessment, we can improve patients’ quality of life during their admission for the transplant. Considering the positive feedback from patients, we plan to conduct a formal prospective study evaluating the impact of palliative care on adult stem cell transplant patients at our institution. By addressing the patient’s whole person rather than just their disease, we also hope to decrease number of admissions as well as length of stay. Ultimately, we look forward to expanding this to other malignancies as well.
Association between decline of neutrophil-to-eosinophil ratio (NER) at week 6 after ipilimumab plus nivolumab initiation and improved clinical outcomes in metastatic renal cell carcinoma (mRCC).
Authors: Yu-Wei Chen, Matthew D Tucker, Landon Carter Brown, Hesham Abdallah Yasin, Kristin Kathleen Ancell, Andrew J. Armstrong, Katy Beckermann, Nancy B. Davis, Michael Roger Harrison, Elizabeth Kaiser, Renee McAlister, Kerry Schaffer, Deborah Wallace, Daniel J. George, Wendy Kimryn Rathmell, Brian I. Rini, Tian Zhang
Journal: Journal of Clinical Oncology (2022)

4527 Background: Low baseline NER has been associated with improved response to immunotherapy in mRCC (PMID:34732251). The current study aimed to investigate the early decline of NER at week 6 after ipilimumab/nivolumab (ipi/nivo) initiation and treatment responses in mRCC. Methods: Retrospective chart review of ipi/nivo-treated mRCC patients at Vanderbilt-Ingram Cancer Center and Duke Cancer Institute was conducted. Landmark analysis at week 6 after ipi/nivo initiation was performed to assess the association between change in NER and clinical responses [progression-free survival (PFS)/overall survival (OS)]. Results: There were 150 mRCC patients included in the analysis: 78% had clear cell histology, 78% were IMDC intermediate/poor risk, and 74% were male. The median follow-up time was 11.9 months. After ipi/nivo initiation, the median NER decreased from 23.8 (interquartile range: 15.0-57.1) at baseline to 19.8 (10.6-40.8) at week 6; 102 (68%) patients had decreased NER. The NER at week 6 was grouped by percent change (≥ 50% decrease vs &lt;50% decrease vs increase). In multivariable regression analysis after adjustment for age, sex, race, IMDC risk group, baseline NER, histology, prior systemic therapy, and prior nephrectomy (Table), decreased NER ≥ 50% was associated with improved PFS [adjusted hazard ratio (AHR): 0.55, p-value: 0.03] and OS (AHR: 0.38, p-value: 0.02) (Table). Stratified analysis was conducted by baseline NER [≥vs &lt; baseline median NER (23.8)]: decreased NER ≥ 50% was associated with improved PFS (AHR: 0.46, p-value: 0.048) and OS (AHR: 0.29, p-value: 0.01) in the subgroup with high baseline NER. These associations were not observed in the subgroup with low baseline NER (p-value for PFS: 0.25; p-value for OS: 0.61). Conclusions: The decline of NER ≥50% at week 6 after ipi/nivo initiation was associated with improved PFS/OS in mRCC patients with high baseline NER. Prospective studies are warranted to validate NER change as a biomarker to predict response to ICIs in mRCC. [Table: see text]
Nomogram to predict duration of clinical benefit from nivolumab in platinum resistant, recurrent/metastatic head and neck squamous cell carcinoma.
Authors: Laura Feeney, Samuel Rack, Hitesh Mistry, Becky Bola, Andrew McPartlin, Andrew Sykes, Robert Metcalf
Journal: Journal of Clinical Oncology (2022)

e18016 Background: Immune checkpoint blockade of the programmed death-1 receptor (PD1) with nivolumab improves survival for patients with platinum resistant recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, response rates are only 15-20% and the majority of patients do not have prolonged clinical benefit. Established predictive biomarkers such as PDL1 are not reliable in this context and there remain no reliable predictors of response to nivolumab in R/M HNSCC. We therefore sought to evaluate a panel of clinical, haematology and biochemistry parameters to develop a nomogram to predict the duration of clinical benefit following treatment with nivolumab. Methods: Ninety-one patients treated with nivolumab for R/M HNSCC were included. Nivolumab was administered as standard of care management and tumour response was evaluated every 8-12 weeks using CT or MRI. The electronic clinical records were reviewed and all clinical and demographic data were extracted in addition to baseline haematology and clinical biochemistry values. Using Cox proportional hazard analysis these variables were used to create a predictive model for duration of clinical benefit. Patients were dichotomised based upon duration on nivolumab treatment. Backwards elimination with a p-value threshold of 0.05 was used to create a predictive nomogram. For the final model, patients were assigned to two groups (&lt; 3 months and ≥ 3 months on therapy) calculated from the date of first nivolumab dose to the date of discontinuation. Progression free survival (PFS) and overall survival (OS) were calculated from the date of the first dose of nivolumab. Results: Of the 91 patients, 82 had stopped treatment at the time of analysis with a median time on treatment of 2.5 months (95% CI 1.8 to 3.6). Median PFS was 3 months with 1-year PFS rate of 15%. Median OS was 9 months with 1 year OS rate of 40%. Multivariable analysis identified multiple pre-treatment factors that correlate with time on treatment; age (HR 0.97; 95% CI 0.93-1.00, p = 0.029), oropharyngeal tumour location (HR 0.51; 95% CI 0.31-0.85, p = 0.01), N stage (HR 1.84; 95% CI 0.97-3.5, p = 0.061), M stage (HR 2.44; 95% CI 1.27-4.7, p = 0.007), and pre-treatment peripheral blood markers which included monocyte count (HR 2.83; 95% CI 1.05-7.6, p = 0.04), sodium (HR 0.94; 95% CI 0.88-1.00, p = 0.057) and calcium (HR 7.6; 95% CI 1.46-39.7, p = 0.016) levels. These were included in the final nomogram which had a concordance index of 0.69. Conclusions: We have developed a novel nomogram to predict the duration of clinical benefit from nivolumab in platinum resistant R/M HNSCC for subsequent independent validation. This may assist clinicians in counselling patients and clinical decision making and could also be used to identifying poor responders for whom alternative treatment options are required.